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PubMed2000

Ability of the VITEK 2 advanced expert system To identify beta-lactam phenotypes in isolates of Enterobacteriaceae and Pseudomonas aeruginosa.

The Advanced Expert System (AES) was used in conjunction with the VITEK 2 automated antimicrobial susceptibility test system to ascertain the beta-lactam phenotypes of 196 isolates of the family Enterobacteriaceae and the species Pseudomonas aeruginosa. These isolates represented a panel of strains that had been collected from laboratories worldwide and whose beta-lactam phenotypes had been characterized by biochemical and molecular techniques. The antimicrobial susceptibility of each isolate was determined with the VITEK 2 instrument, and the results were analyzed with the AES to ascertain the beta-lactam phenotype. The results were then compared to the beta-lactam resistance mechanism determined by biochemical and molecular techniques. Overall, the AES was able to ascertain a beta-lactam phenotype for 183 of the 196 (93.4%) isolates tested. For 111 of these 183 (60.7%) isolates, the correct beta-lactam phenotype was identified definitively in a single choice by the AES, while for an additional 46 isolates (25.1%), the AES identified the correct beta-lactam phenotype provisionally within two or more choices. For the remaining 26 isolates (14.2%), the beta-lactam phenotype identified by the AES was incorrect. However, for a number of these isolates, the error was due to remediable problems. These results suggest that the AES is capable of accurate identification of the beta-lactam phenotypes of gram-negative isolates and that certain modifications can improve its performance even further.

Enterobacteriaceae↗
PubMed2002

Discordance between genotypic and phenotypic drug resistance profiles in human immunodeficiency virus type 1 strains isolated from peripheral blood mononuclear cells.

The aim of the study was to analyze the relationship between genotypic and phenotypic drug resistance profiles of human immunodeficiency virus type 1 (HIV-1) strains isolated from patients during double-analogue nucleoside therapy. A drug-resistant HIV strain was isolated from 20 out of 25 patients, with 16 (64%) subjects carrying a virus with multiple drug resistance mutations. The most frequent resistance mutations were M184V (18 isolates) and M41L (7 isolates). Discordance between the genotypic and phenotypic profile for at least one drug was detected in 16 out of 25 strains. Particularly, eight isolates had a discordant genotypic-phenotypic resistance pattern for two drugs and one isolate had such a pattern for three drugs. A genotypic resistance pattern with a phenotypic sensitivity profile was detected in six isolates (four resistant to zidovudine and two resistant to lamivudine). On the other hand for several strains a genotypic pattern of sensitivity pattern to abacavir (10 strains), didanosine (7 strains), stavudine (3 strains), zidovudine (2 strains), and lamivudine (1 strain) with a phenotypic resistance profile was detected. After a follow-up period of 8 months, an impairment of virological and immunological parameters was detected only in subjects with an HIV-1 isolate with a phenotypic resistance profile in despite of the genotypic results. Predicting resistance phenotype from genotypic data has important limitations. Despite the low number of patients and the short follow-up period, this study suggests that during failing therapy with analogue nucleosides, a phenotypic analysis could be performed in spite of an HIV genotypic sensitivity pattern.

Anti-HIV Agents↗
PubMed2026

Evaluation of Oxford nanopore sequencing for antimicrobial resistance surveillance in Salmonella: comparison with phenotypic antimicrobial susceptibility in a large-scale study.

UNLABELLED: Salmonella is a major zoonotic foodborne pathogen, and antimicrobial resistance (AMR) in Salmonella presents a significant public health challenge. Compared with conventional antimicrobial susceptibility testing (AST), whole-genome sequencing (WGS) provides a more rapid and comprehensive approach to AMR characterization, thereby informing antimicrobial selection and supporting public health surveillance. In this study, Oxford Nanopore Technology (ONT)-based WGS was performed on 1,490 Salmonella isolates collected through nationwide surveillance in Taiwan in 2025. Genotypic resistance inferred from WGS data was compared with phenotypic AST results to assess the performance of ONT-WGS. Overall, WGS-inferred resistance showed high concordance with phenotypic resistance for most antimicrobials. However, major genotype-phenotype discordance was observed, attributed to four categories: (i) breakpoint-dependent classification, (ii) reduced or absent phenotypic expression of resistance genes, (iii) minimum inhibitory concentration (MIC) modulation by ramAp, and (iv) absence of known AMR determinants. Notable discrepancies included tigecycline resistance without known genetic determinants, nalidixic acid resistance linked to ramAp-mediated MIC elevation, and a high prevalence of colistin resistance (35.7%) in S. Enteritidis, with most resistant isolates lacking identifiable AMR determinants. Additionally, a significant proportion of ESBL- and AmpC-producing isolates were classified as susceptible or intermediate to cefotaxime and ceftazidime under CLSI criteria, highlighting the potential for misclassification and treatment failure. These findings demonstrate that ONT-WGS enables accurate and comprehensive AMR characterization by directly identifying resistance determinants and avoiding potential misclassification associated with breakpoint-based AST interpretations. When interpreted appropriately, WGS can support better antimicrobial selection and serve as a valuable alternative to conventional susceptibility testing. IMPORTANCE: Accurate prediction of antimicrobial resistance is essential for appropriate therapy and effective surveillance of Salmonella. However, discordance between genotype-based predictions and phenotypic antimicrobial susceptibility testing (AST) can complicate clinical interpretation. In this nationwide study of 1,490 Salmonella isolates, we show that Oxford Nanopore Technology-based whole-genome sequencing (ONT-WGS) provides rapid and comprehensive detection of antimicrobial resistance determinants with high concordance to phenotypic AST. We further identify four major mechanisms underlying genotype-phenotype discordance, including breakpoint-dependent classification, reduced or absent phenotypic expression of resistance genes, minimum inhibitory concentration (MIC) modulation by ramAp, and the absence of known AMR determinants. These findings demonstrate how WGS can complement conventional AST, improve interpretation of challenging susceptibility results, and strengthen genomic surveillance of emerging antimicrobial-resistant Salmonella.

Microbial Sensitivity Tests↗
PubMed2004

Correlation of long term phenotypic and clinical outcomes following limbal epithelial transplantation cultivated on amniotic membrane in rabbits.

AIM: To determine the epithelial phenotype in rabbits with total limbal stem cell deficiency (LSCD) after reconstruction with autologous limbal epithelial stem cells ex vivo expanded on rabbit amniotic membrane (AM). METHODS: Left eyes of 52 rabbits were rendered total LSCD, verified by impression cytology. The fibrovascular pannus of each cornea was removed. Group I (n = 10) received rabbit AM transplantation alone, while groups II-IV (n = 42) underwent transplantation of LSC cultured on rabbit AM (LSC-AM) from a small limbal biopsy taken from the right eye. Clinical outcome was graded as "success," "partial success," or "failure" depending on the corneal smoothness and avascularity. Epithelial phenotype was determined by immunostaining and graded as "corneal (K)," "conjunctival (J)," or "mixed (M)" depending on expression of K3 and Muc5AC. RESULTS: After 1 year follow up, group I showed 100% failure and groups II-IV showed 26% success (p<0.001). Clinical failure correlated with J phenotype p = 0.001), while clinical success correlated with K phenotype p = 0.01). When the phenotypic outcome was used for comparison, J phenotype was significantly high in group I (p = 0.003), while K phenotype was significantly high in groups II-IV (p<0.05). CONCLUSION: There is a strong correlation between clinical success and resultant corneal epithelial phenotype. Ex vivo expanded LSC can successfully reconstruct corneal surfaces with unilateral total LSCD.

Amnion↗
PubMed2006

Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas.

PURPOSE: Basal-like phenotype tumors are frequently found among BRCA1 germ-line mutated breast carcinomas. They are biologically aggressive and have a tendency towards visceral metastasis when untreated. Nevertheless, it has been suggested that they respond to chemotherapy better than other types of tumors. Fascin expression has been associated with lung metastasis in breast cancer. The aim of this study was to determine whether basal-like phenotype and fascin were related in both sporadic and familial tumors and with prognosis in node-negative sporadic breast cancers. EXPERIMENTAL DESIGN: 230 nonfamilial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analyzed using tissue microarrays. Tumors that were estrogen receptor/HER2 negative and cytokeratin 5/6 and/or epidermal growth factor receptor positive were considered to have a basal-like phenotype. RESULTS: A basal-like phenotype was found in 11.9% of sporadic cancers. Among patients not receiving adjuvant chemotherapy, a basal-like phenotype was associated with poor prognosis (P = 0.001, log-rank test) whereas no such association was found in patients receiving it. Tumors with a basal-like phenotype showed local recurrence (17.4%) or visceral metastasis (13%) but not bone metastasis (P = 0.001). Fascin expression was observed in 25.1% of sporadic invasive breast carcinomas and was associated with the basal-like phenotype, but not with prognosis or recurrence pattern. Fascin was expressed in 83.3% and 16.7% BRCA1- and BRCA2-associated carcinomas, respectively (P = 0.048). CONCLUSIONS: Basal-like tumors had a tendency towards visceral metastasis and their prognosis was dependent on the use of postoperative chemotherapy. Although fascin expression was associated with the basal-like phenotype, it was not associated with their metastatic behavior. Fascin expression is frequent in BRCA1-associated tumors.

Actins↗
PubMed2005

Genotype-phenotype correlation in Italian families with Stargardt disease.

Autosomal recessive Stargardt disease (STGD) has been associated with substantial genetic and phenotypic heterogeneity. By systematic clinical analyses of STGD patients with complete genetic data (i.e. identified mutations on both alleles of the ABCA4 gene), we set out to determine phenotypic subtypes and to correlate these with specific ABCA4 alleles. Twenty-eight patients from 18 families with STGD/fundus flavimaculatus were investigated. All patients were submitted to complete ophthalmologic examination, electrophysiology, fluorescein angiography and ABCA4 gene chip analysis. Two main clinical phenotypes were observed among the examined patients. The severe phenotype was characterized by the onset of the disease <20 years and reduced ERG response, whereas the mild phenotype presented with later onset of the disease and a normal ERG response. Genetic analysis of the ABCA4 gene revealed, in the severe group, more frequently deletions, stop codons and insertions as compared to the mild phenotype group (p=0.0113 by Fisher's exact test). Moreover, the compound heterozygous mutations G1961E/5018+2T-->C found in 7 patients from 3 unrelated STGD families were associated with a mild phenotype in all subjects, except 1. This study documented variability of the clinical expression of STGD in relation to the age of onset of the disease, fundus appearance and the ERG response and allowed to subdivide patients into a severe and a mild phenotype group. These findings suggest that an extensive and comprehensive genetic analysis of STGD patients combined with thorough clinical evaluation, including the careful recording of the age of onset of the disease, would allow a more precise prognostic evaluation.

ATP-Binding Cassette Transporters↗
PubMed1990

Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk.

In a community-based study of 301 subjects from 61 nuclear families, two distinct phenotypes (denoted A and B) were identified by nondenaturing gradient gel electrophoretic analysis of low density lipoprotein (LDL) subclasses. Phenotype A was characterized by predominance of large, buoyant LDL particles, and phenotype B consisted of a major peak of small, dense LDL particles. Previous analysis of the family data by complex segregation analysis demonstrated that these phenotypes appear to be inherited as a single-gene trait. In the present study, the phenotypes were found to be closely associated with variations in plasma levels of other lipid, lipoprotein, and apolipoprotein measurements. Specifically, phenotype B was associated with increases in plasma levels of triglyceride and apolipoprotein B, with mass of very low and intermediate density lipoproteins, and with decreases in high density lipoprotein (HDL) cholesterol, HDL2 mass, and plasma levels of apolipoprotein A-I. Thus, the proposed genetic locus responsible for LDL subclass phenotypes also results in an atherogenic lipoprotein phenotype.

Adolescent↗
PubMed1973

Hyperlipidemia in coronary heart disease. 3. Evaluation of lipoprotein phenotypes of 156 genetically defined survivors of myocardial infarction.

Although analysis of lipoprotein phenotypes is widely used to diagnose and classify the familial hyperlipidemias, an evaluation of this system as a method for genetic classification has hitherto not been published. The present study of 156 genetically defined survivors of myocardial infarction was therefore designed to examine the relationship between lipoprotein phenotypes and genetic lipid disorders. The lipoprotein phenotypes of each survivor was determined primarily by measurement of his plasma triglyceride and low density lipoprotein (LDL)-cholesterol concentrations; his genetic disorder was identified by analysis of whole plasma cholesterol and triglyceride levels in relatives. The mean levels of LDL-cholesterol discriminated statistically among the three monogenic lipid disorders; it was highest in survivors with familial hypercholesterolemia (261+/-61 mg/100 ml [mean +/-SD]); intermediate in those with familial combined hyperlipidemia (197+/-50); and lowest in those with familial hypertriglyceridemia (155+/-36) (P < 0.005 among the three groups). However, on an individual basis no lipoprotein pattern proved to be specific for any particular genetic lipid disorder; conversely, no genetic disorder was specified by a single lipoprotein pattern. This lack of correlation occurred for the following reasons: (a) individual LDL-cholesterol levels frequently overlapped between disorders; (b) in many instances a small quantitative change in the level of either LDL-cholesterol or whole plasma triglyceride caused qualitative differences in lipoprotein phenotypes, especially in individuals with familial combined hyperlipidemia, who showed variable expression (types IIa, IIb, IV, or V); (c) lipoprotein phenotypes failed to distinguish among monogenic, polygenic, and sporadic forms of hyperlipidemia; (d) clofibrate treatment of some survivors with genetic forms of hyperlipidemia caused their levels of triglyceride and LDL-cholesterol to fall below the 95th percentile, thus resulting in a normal phenotype; and (e) beta-migrating very low density lipoproteins (beta-VLDL), previously considered a specific marker for the type III hyperlipidemic disorder, was identified in several survivors with different lipoprotein characteristics and familial lipid distributions. These studies indicate that lipoprotein phenotypes are not qualitative markers in the genetic sense but instead are quantitative parameters which may vary among different individuals with the same genetic lipid disorder. It would therefore seem likely that a genetic classification of the individual hyperlipidemic patient with coronary heart disease made from a quantitative analysis of lipid levels in his relatives may provide a more meaningful approach than determination of lipoprotein phenotypes.

Adult↗
PubMed1994

Haptoglobin phenotypes and gene frequencies in unipolar major depression.

OBJECTIVE: Studies from the authors' laboratory have shown that major depression is accompanied by significantly increased plasma concentrations of positive acute-phase proteins such as haptoglobin. Haptoglobin is characterized by a molecular variation with three known phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2). This study investigated haptoglobin plasma levels and phenotype and gene frequencies in unipolar major depression. METHOD: Haptoglobin plasma levels of 22 healthy volunteers, 32 patients with minor depression, and 72 patients with major depression were determined by means of a laser nephelometric method. Haptoglobin phenotyping of these 126 subjects and 200 healthy blood donors was also carried out. RESULTS: The patients with major depression exhibited significantly higher haptoglobin plasma levels than the healthy comparison subjects and the patients with minor depression. Subjects with the haptoglobin phenotype Hp 2-2 had significantly lower haptoglobin levels than the phenotype Hp 1-1 and Hp 2-1 carriers. The frequencies of haptoglobin phenotypes Hp 2-1 (61.1%) and Hp 2-2 (20.8%) in the patients with major depression were significantly higher and lower, respectively, than the frequencies in the normal population (i.e., the blood donors: 48.0% and 37.0%, respectively). The frequency of the Hp-1 gene was significantly greater in the patients with major depression (48.6%) than in the normal population (39.0%). CONCLUSIONS: Major depression is characterized by a hyperhaptoglobinemia that is largely independent of haptoglobin phenotypes. This altered distribution of haptoglobin phenotypes and genes suggests that genetic variation on chromosome 16 may be associated with that illness.

Adult↗
PubMed2002

Acetylator phenotype and genotype in HIV-infected patients with and without sulfonamide hypersensitivity.

Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow acetylator phenotype are predisposed to these reactions, whereas other studies suggest that the slow acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow acetylator phenotype, while 8 of 14 patients (57%) without such a history exhibited this same phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow acetylator phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between acetylator genotype and phenotype.

Acetylation↗
PubMedDate not supplied

Genotype and phenotype relationship in MLSb resistance in Streptococcus pyogenes and Streptococcus agalactiae isolated in central Italy.

The aim of this work is to study a correlation between phenotype and genotype in clinical isolates of erythromycin-resistant Streptococcus spp. Among the 25 erythromycin-resistant S. pyogenes, we detected six strains with iMLSB, nine with cMLSB and two with M phenotypes. Among 14 erythromycin-resistant S. agalactiae, we detected five strains with iMLSB, seven with cMLSB and none with an M phenotype. Moreover, 8 S. pyogenes and 2 S. agalactiae showed a phenotype not matching the known ones described in literature, defining an unknown phenotype. Upon examination, the genetic profiles, erm(A), erm(B) and mef(A), of the clinical isolates did not easily correlate with a specific phenotype. Our findings highlighted that the whole matter of phenotypic diversity in macrolide-resistant S. pyogenes and S. agalactiae strains and the correlation with their genetic profiles should be submitted to a more careful analysis of phenotypic and genotypic characterization.

Anti-Bacterial Agents↗
PubMed2003

Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study.

The relationship between elevated blood pressure and cardiovascular and cerebrovascular disease risk is well accepted. Both systolic and diastolic hypertension are associated with this risk increase, but systolic blood pressure appears to be a more important determinant of cardiovascular risk than diastolic blood pressure. Subjects for this study are derived from the Framingham Heart Study data set. Each subject had five records of clinical data of which systolic blood pressure, age, height, gender, weight, and hypertension treatment were selected to characterize the phenotype in this analysis. We modeled systolic blood pressure as a function of age using a mixed modeling methodology that enabled us to characterize the phenotype for each individual as the individual's deviation from the population average rate of change in systolic blood pressure for each year of age while controlling for gender, body mass index, and hypertension treatment. Significant (p = 0.00002) evidence for linkage was found between this normalized phenotype and a region on chromosome 1. Similar linkage results were obtained when we estimated the phenotype while excluding values obtained during hypertension treatment. The use of linear mixed models to define phenotypes is a methodology that allows for the adjustment of the main factor by covariates. Future work should be done in the area of combining this phenotype estimation directly with the linkage analysis so that the error in estimating the phenotype can be properly incorporated into the genetic analysis, which, at present, assumes that the phenotype is measured (or estimated) without error.

Age Factors↗
PubMed1999

Genotype and intellectual phenotype in untreated phenylketonuria patients.

Previous studies have shown that genotype correlates with biochemical phenotype in treated phenylketonuria. If there is a strong correlation between genotype and intellectual phenotype of untreated patients, it would be possible to determine which individuals would have normal intelligence without treatment. In this study, 42 families with untreated phenylketonuria were analyzed to examine whether there was an association between genotype and untreated intellectual phenotype. Previously 12 of the 42 families were genotyped; now the genotyping of these patients is almost complete (40/42), a more thorough investigation was possible. Although the predicted phenylalanine hydroxylase (PAH) enzyme activity, based on genotype, showed an association with the patients' intellectual phenotype, the extensive overlap between the groups means the association is of little clinical value. Unrelated individuals with the same genotype and also siblings were found to have very different intellectual phenotypes. These phenotypic differences could not be explained by a difference in diet; therefore, we propose that another gene or genes may be modifying the intellectual phenotype of untreated patients. A preliminary search for possible modifying genes was performed. The possibility that a modifying gene was linked to the PAH gene on chromosome 12 was investigated using markers closely linked to the gene; however, no evidence for a modifying gene close to the PAH gene was found. Tyrosine hydroxylase was chosen as a candidate gene, because it can perform the same reaction as PAH. Using a common polymorphism within the gene, we found that this gene did not cause the discordant results and thus, did not modify the PAH phenotype.

Amino Acid Substitution↗
PubMed1989

Keratin expression in human mammary epithelial cells cultured from normal and malignant tissue: relation to in vivo phenotypes and influence of medium.

The luminal and basal epithelial cells in the human mammary gland can be distinguished in tissue sections on the basis of the pattern of keratins they express. Moreover, the invasive cells in primary carcinomas show a keratin profile that corresponds to that of the dominant luminal cell (7, 8, 18, 19). When homogeneous populations of luminal epithelial cells from milk or from breast cancer metastases are cultured the profile of keratin expression seen in vivo is maintained. We have therefore used monospecific antibodies reactive with individual keratins to examine the phenotype of cells cultured in three different media from reduction mammoplasty tissue that contains both luminal and basal cells. The phenotype of cells cultured from primary breast cancers in one of these media (MCDB170) has also been examined. In characterizing cell phenotypes, antibodies to a polymorphic epithelial mucin (PEM) expressed in vivo by luminal cells, and to smooth muscle (a) actin, expressed in vivo by basal cells, have also been used. Our results show that proliferation of different cell phenotypes is selected for in different media. In milk mix (MX) developed for growth of luminal cells from milk, only the luminal cell phenotype proliferates (for only 1 or 2 passages). In medium MCDB 170, which was developed for long-term growth of human mammary epithelial cells from reduction mammoplasty organoids, cells from the basal layer proliferate, while in MM medium the basal phenotype dominates, but a few cells with the luminal phenotype are found. Around passage 3, in medium MCDB 170, most cells senesce and a subpopulation of cells proliferates on further passage. These cells retain expression of the basal epithelial keratins but also express some features characteristic of luminal epithelial cells, suggesting that the basal layer may contain a stem cell that can develop along the luminal lineage. In culture, however, they do not express keratin 19, which in vivo is a feature of the fully differentiated luminal cell. The cells cultured from primary breast cancer in medium MCDB 170 have a similar keratin profile to that of the normal cells cultured in this medium. They do not express keratin 19, even though the invasive cells in primary cancers homogeneously express this keratin in vivo. The invasive phenotype, which in its keratin profile corresponds to the differentiated luminal cell and that of the metastatic cancer lines, cannot be cultured from primary breast cancers using MX, which supports proliferation of the corresponding normal cell.

Breast↗
PubMed2006

The evolutionary consequences of ecological interactions mediated through phenotypic plasticity.

Phenotypic plasticity describes the capacity of a genotype to exhibit a range of phenotypes in response to variation in the environment. Environmental variation encompasses both abiotic and biotic components of the environment, including interactions among organisms. The strength and outcome of many ecological interactions, ranging from antagonism to mutualism, are mediated through the phenotypically plastic responses of one or more players in the interaction. Herein, three broadly defined, non-mutually exclusive, evolutionary consequences of ecological interactions mediated through phenotypic plasticity are discussed. (1) The predictable plastic response of one partner can favor behaviors, physiological responses, and life history traits of an interacting partner that manipulate, circumvent, or ameliorate the response of that partner. (2) Phenotypic plasticity can generate substantial spatial and temporal variation within and among populations. Such phenotypic variation can depend on the density and identity of interacting players in an ecological community, and can ultimately affect the evolutionary outcome of ecological interactions. (3) Phenotypic plasticity affects the strength and direction of natural selection. Ecological interactions mediated through phenotypic plasticity are ubiquitous in nature, and the potential evolutionary consequences of these interactions illustrate the complexity inherent in understanding evolution in a community context.

Adaptation, Physiological↗
PubMed2004

Adjusting data to body size: a comparison of methods as applied to quantitative trait loci analysis of musculoskeletal phenotypes.

UNLABELLED: The aim of this study was to compare three methods of adjusting skeletal data for body size and examine their use in QTL analyses. It was found that dividing skeletal phenotypes by body mass index induced erroneous QTL results. The preferred method of body size adjustment was multiple regression. INTRODUCTION: Many skeletal studies have reported strong correlations between phenotypes for muscle, bone, and body size, and these correlations add to the difficulty in identifying genetic influence on skeletal traits that are not mediated through overall body size. Quantitative trait loci (QTL) identified for skeletal phenotypes often map to the same chromosome regions as QTLs for body size. The actions of a QTL identified as influencing BMD could therefore be mediated through the generalized actions of growth on body size or muscle mass. MATERIALS AND METHODS: Three methods of adjusting skeletal phenotypes to body size were performed on morphologic, structural, and compositional measurements of the femur and tibia in 200-day-old C57BL/6J x DBA/2 (BXD) second generation (F(2)) mice (n = 400). A common method of removing the size effect has been through the use of ratios. This technique and two alternative techniques using simple and multiple regression were performed on muscle and skeletal data before QTL analyses, and the differences in QTL results were examined. RESULTS AND CONCLUSIONS: The use of ratios to remove the size effect was shown to increase the size effect by inducing spurious correlations, thereby leading to inaccurate QTL results. Adjustments for body size using multiple regression eliminated these problems. Multiple regression should be used to remove the variance of co-factors related to skeletal phenotypes to allow for the study of genetic influence independent of correlated phenotypes. However, to better understand the genetic influence, adjusted and unadjusted skeletal QTL results should be compared. Additional insight can be gained by observing the difference in LOD score between the adjusted and nonadjusted phenotypes. Identifying QTLs that exert their effects on skeletal phenotypes through body size-related pathways as well as those having a more direct and independent influence on bone are equally important in deciphering the complex physiologic pathways responsible for the maintenance of bone health.

Animals↗
PubMed2006

Phenotypic plasticity opposes species invasions by altering fitness surface.

Understanding species invasion is a central problem in ecology because invasions of exotic species severely impact ecosystems, and because invasions underlie fundamental ecological processes. However, the influence on invasions of phenotypic plasticity, a key component of many species interactions, is unknown. We present a model in which phenotypic plasticity of a resident species increases its ability to oppose invaders, and plasticity of an invader increases its ability to displace residents. Whereas these effects are expected due to increased fitness associated with phenotypic plasticity, the model additionally reveals a new and unforeseen mechanism by which plasticity affects invasions: phenotypic plasticity increases the steepness of the fitness surface, thereby making invasion more difficult, even by phenotypically plastic invaders. Our results should apply to phenotypically plastic responses to any fluctuating environmental factors including predation risk, and to other factors that affect the fitness surface such as the generalism of predators. We extend the results to competition, and argue that phenotypic plasticity's effect on the fitness surface will destabilize coexistence at local scales, but stabilize coexistence at regional scales. Our study emphasizes the need to incorporate variable interaction strengths due to phenotypic plasticity into invasion biology and ecological theory on competition and coexistence in fragmented landscapes.

Adaptation, Physiological↗
PubMed1995

Effect of cigarette smoking on pulmonary function in each phenotype M of alpha-1-protease inhibitor.

Human alpha-1-protease inhibitor (alpha-1-Pi) has been known to be a highly polymorphic protein. We hypothesized that antiprotease activity of each phenotype M of alpha 1-protease inhibitor (PiM) might be different among smokers and that a variation of decrease in pulmonary function for a given amount of cigarette smoking might be associated with PiM phenotypes. To test this, we investigated the effect of cigarette smoking on pulmonary function in each PiM phenotype. The serum level of alpha 1-Pi was measured by the turbidimetric immunoassay and the distribution of PiM phenotypes was determined using isoelectric focusing technique in 247 healthy subjects and 20 COPD patients. Serum levels of alpha-1-antitrypsin of healthy and COPD subjects were 205.1 +/- 31.1 and 179.2 +/- 44.4 (+/- SD) mg/dL, respectively (p > 0.01). The frequency of each PiM phenotype in healthy subjects was shown as follows: M1, 0.555; M1M2, 0.328; M2, 0.041; M1M3, 0.057; M2M3, 0.016; M3, 0.004. The difference in the distribution of PiM phenotypes between healthy and COPD subjects was not significant. Single- and multiple-regression analyses showed that the ratio of FEV1 to forced vital capacity (FVC), in which FEV1 is expressed as percentage of FVC, the maximum flow rate at 50% of FVC divided by measured body height (V50/Ht), and the maximum flow rate at 25% of FVC divided by body height (V25/Ht) were closely related to age and that V25/Ht also was related to smoking index. However, PiM phenotype was unrelated to those pulmonary function variables. We conclude that PiM phenotype is not a major determinant of difference in magnitude of pulmonary impairments caused by cigarette smoking in each individual.

Adult↗